Insulin resistance is a condition in which the body produces insulin, a hormone made by the pancreas, but the muscle, fat and liver cells do not respond to insulin properly. Insulin helps to lower blood sugars (glucose) in the body after a meal. When the cells fail to respond adequately to circulating insulin, glucose levels rise, and the body needs to produce an increased amount of insulin to maintain the blood glucose in the normal range. Therefore, people with insulin resistance have elevated circulating levels of insulin. If the pancreas cannot keep up with the increased demand for insulin, type 2 diabetes can develop with high levels of both glucose and insulin circulating in the blood at the same time. Insulin resistance is also associated with an increased risk for developing heart disease.

Polycystic Ovary Syndrome causes hormonal imbalances leading to irregular menstrual cycles, excess facial and body hair, weight gain and adult acne. Women with PCOS also have insulin resistance and are at high risk for developing type 2 “We’re one of the top institutions worldwide looking at the connection between PCOS and insulin resistance,” said John Nestler, M.D., the William Branch Porter Professor and chair of the Department of Internal Medicine at the VCU School of Medicine. “Our ongoing research is investigating the influence of insulin on fertility.”

In the 1980s, Nestler was among the first scientists in the world to suggest that insulin was an important reproductive hormone. His pioneering work to induce ovulation through the use of such insulin-sensitizing drugs as metformin has led to the common use of metformin to treat infertility in women with PCOS.

“We know metformin can be an effective fertility treatment for most women with PCOS. However, we have found that some women don’t respond to metformin, and we want to know why. We think it may be related to individual genetic differences and gene variation in enzymes affected by metformin. This variation in specific genes may explain why metformin is not an effective treatment for some women,” said Nestler.

Nestler and his research team are currently focusing on pharmacogenomics, which is the study of how the actions of and reactions to drugs vary with individuals. The implication of this research is that based on the genetic profile of a patient, a physician may be able to discern whether the patient should be on metformin or not and would be able to apply therapy for PCOS more effectively.

This research is funded through a U54 grant from the National Institutes of Health. The center grant includes three main projects studying PCOS, including the work by Nestler and his team. For more information about PCOS research at VCU, visit www.vcu.edu/pcos.

About VCU and the VCU Medical Center

Virginia Commonwealth University is a major, urban public research university with national and international rankings in sponsored research. Located in downtown Richmond, VCU enrolls more than 31,000 students in 222 degree and certificate programs in the arts, sciences and humanities. Sixty-six of the programs are unique in Virginia, many of them crossing the disciplines of VCU’s 13 schools and one college. MCV Hospitals and the health sciences schools of Virginia Commonwealth University compose the VCU Medical Center, one of the nation’s leading academic medical centers. For more, see www.vcu.edu.

More women than men die from heart disease each year. This suggests that the cardiovascular system of men and women functions differently.

“Our lab has been interested in examining whether or not the response to stress, in particular mental stress, is different, which might be one explanation why women die at a higher rate,” said Edmund O. Acevedo, Ph.D., chair and professor of the Department of Health and Human Performance in the Virginia Commonwealth University School of Education.

In ongoing research, Acevedo and his team introduced human subjects to lab-induced stressors, including computer tasks, mental arithmetic and the Stroop color word task.

“They’re simple tasks anybody can do,” he explained. Yet men and women react differently to the mental stress. “In males, these tasks elicit a greater blood pressure response. We call that a vascular reaction. In females, a greater increase in heart rate, which is a cardiac response.”

To better understand the body’s reaction, the researchers draw blood periodically from their subjects and examine it in an attempt to distinguish unique inflammatory markers that help to explain the difference in cardiovascular response.

Acevedo also is interested in obesity and physical activity and the impact of pro-inflammatory response.

“Ours was the first lab to demonstrate pro-inflammatory response linked to BMI (body mass index),” Acevedo said. “Our intention is a greater understanding of how obesity and physical activity ameliorate or attenuate cardiac and vascular reactions. The lab has completed studies in lean and obese males, and we hope to extend our data collection on females,” he said. The VCU Presidential Research Initiatives Program and VCU School of Nursing are providing funding. Principal investigator for the male subjects is assistant professor R. Lee Franco, Ph.D., in the School of Education, and for the female subjects is associate professor Dr. Kyungeh An, Ph.D., in the School of Nursing.

In the past, Acevedo’s research broadly looked into human performance, including physiological reactions to the stress of exercise. More recently, his approach has evolved into studies that can have an impact on more people, leading him to address health issues. The gender differences in heart disease rates and current treatment approaches, led him into this realm.

“As a scientist, (the gender difference in heart disease rates) is an interesting, intriguing question. The clinical paradigms were developed for males. How come we do not do something different for women? We don’t understand the differences well enough,” he said.

“We’re adding to the literature of what might be happening. And with that knowledge, someone might eventually develop novel approaches.”

About VCU and the VCU Medical Center

Virginia Commonwealth University is a major, urban public research university with national and international rankings in sponsored research. Located in downtown Richmond, VCU enrolls more than 31,000 students in 222 degree and certificate programs in the arts, sciences and humanities. Sixty-six of the programs are unique in Virginia, many of them crossing the disciplines of VCU’s 13 schools and one college. MCV Hospitals and the health sciences schools of Virginia Commonwealth University compose the VCU Medical Center, one of the nation’s leading academic medical centers. For more, see www.vcu.edu.

As Briana Mezuk, Ph.D., developed her research profile, she encountered a classic “which came first question” – Do the elderly sometimes become depressed because they suffer from old-age illnesses? Or does depression exacerbate the illnesses?

Mezuk, an assistant professor in the Department of Epidemiology and Community Health, focuses her attention on the relationship between mental and physical health. This relationship has an inescapable implication for women, who are two times more likely to develop depression. And according to the National Osteoporosis Foundation, women are 80 percent more likely to develop osteoporosis, a low bone-density condition.

“We need a more holistic view of how psychiatric conditions relate to health,” Mezuk says.

Her current research, based on a grant from the National Institute of Mental Health, examines depression and Type 2 diabetes. It suggests that a relationship between late-life depression and vascular diseases such as diabetes may exist.

“A history of mental health seems to be a stronger predictor of diabetes than the reverse,” she says. “The disease likely doesn’t trigger depression.”

The study uses twin samples to test competing ideas. For example, a common element like stress could immune systems?

“It’s sort of a tomato or tomatoe question,” she says. “Geriatric folks call it frailty. Psychologists call it depression. Losing the quality of life, which frailty would go along with, is a predictor of depression.”

The research grew out of Mezuk’s interest in the links between osteoporosis and depression. The biological reasons for depression, she found, also hurt bones. Often people who are depressed don’t exercise and they suffer from a loss of appetite.

Operating under the assumption that people become depressed because they are sick may be faulty reasoning, Mezuk says. There may be many factors that drive old-age illnesses, including the consequences of behavior that took place years before – including undiagnosed and untreated depression.

“I’m trying to understand these processes,” she says. “What consequences do they have over the life course? How do mental and physical health connect?”

About VCU and the VCU Medical Center

Virginia Commonwealth University is a major, urban public research university with national and international rankings in sponsored research. Located in downtown Richmond, VCU enrolls more than 31,000 students in 222 degree and certificate programs in the arts, sciences and humanities. Sixty-six of the programs are unique in Virginia, many of them crossing the disciplines of VCU’s 13 schools and one college. MCV Hospitals and the health sciences schools of Virginia Commonwealth University compose the VCU Medical Center, one of the nation’s leading academic medical centers. For more, see www.vcu.edu.

Her work adds to the growing base of knowledge of the neurobiological and genetic bases of behavior that put mental illness on par with physical illness. Additionally, research is opening doors to explore novel and effective treatments for mental disorders.

Amstadter is an active researcher in the area of traumatic stress. She looks at genetic predictors of traumatic stress-related conditions and gene-by-environment interactions. She said the anxiety disorder is relatively common and can affect anybody in the population, from young children to older adults. Individuals who experience PTSD generally have a cluster of symptoms including re-experiencing the event, avoiding anything or anyone that is related to or reminds them of the event, feeling emotionally numb following a traumatic event and hyper-vigilance, or being extra alert to any signs of threat.

“PTSD affects approximately 8 percent of the population, but varies depending on the type of trauma a person experiences. For example, events such as physical assault or sexual assault tend to be linked to a higher rate of PTSD than the rates for a motor vehicle accident or a natural disaster,” explained Amstadter.

The treatment of PTSD can involve a variety of psychosocial treatments, including cognitive behavioral therapy, or CBT. This form of therapy does not involve the use of medications. Generally during a CBT counseling session, a therapist will work with an individual to approach the traumatic or feared event and talk about what happened. The therapist can lead the individual to re-experience the traumatic episode in a way that will help them move past the fear to which they have become accustomed.

“One of the hallmark symptoms of PTSD is avoidance. Often times, affected individuals will avoid thinking and talking about the event. They may also likely avoid anything that reminds them of the event,” said Amstadter.

“Unfortunately, this continued avoidance actually doesn’t lead to a natural habituation or a natural getting used to or accepting what happened,” said Amstadter.

Through her research, Amstadter is examining the environmental factors, as well as the biologic and genetic factors, to help understand the post-trauma trajectory of symptoms. For example, her research hopes to help better predict the factors that differentiate individuals who either do not develop symptoms or who experience a naturalistic recovery, from those who develop long-lasting symptoms of a mental health disorder, such as PTSD.

“On the biologic end, we know that about 33 percent of the risk for PTSD is due to genetic factors. We don’t know specifically which genes put people at risk for PTSD and that is what our research is trying to uncover,” said Amstadter.

“If we can determine which genes are involved and understand the effects of a particular variant we may be able to identify people that may need help in the aftermath of a traumatic event,” she said.

Through support from a National Institutes of Health grant, Amstadter and her team are examining the effects of combat history and PTSD status on stress reactivity and subsequent drinking behavior in emerging adults, as well as the role of genetic variants that may play a role in stress-related drinking. Through another NIH grant she is examining the genetic substrates of PTSD in a large epidemiologic study of disaster-exposed youths.

Through her work, she hopes to help to develop an upfront treatment that may prevent PTSD and associated disorders or reduce the suffering of those who encounter it.

In other work, Amstadter is a co-investigator on a research project to develop and determine the effectiveness of a web-based intervention for children and families affected by a disaster.

This article is adapted from 2010 and 2011 VCU University Public Affairs reports on Amstadter’s research.

About VCU and the VCU Medical Center

Virginia Commonwealth University is a major, urban public research university with national and international rankings in sponsored research. Located in downtown Richmond, VCU enrolls more than 31,000 students in 222 degree and certificate programs in the arts, sciences and humanities. Sixty-six of the programs are unique in Virginia, many of them crossing the disciplines of VCU’s 13 schools and one college. MCV Hospitals and the health sciences schools of Virginia Commonwealth University compose the VCU Medical Center, one of the nation’s leading academic medical centers. For more, see www.vcu.edu.

Initially, Dr. Kazuaki Takabe, M.D. and Ph.D, did’t t see himself as a researcher. As a student at Niigata University School of Medicine in Japan, surgery was his passion and molecular biology was only a means to that end.

But he soon found that breast cancer posed more questions than surgery alone could answer. The statistical reality that 1 in 8 U.S. women will develop breast cancer in her lifetime became a powerful motivator to discover why cancer spreads.

Takabe travels between the worlds of surgery and research, dividing his time between the operating room and the lab, where he is investigating the role of Sphingosine-1 phosphate (S1P) in cancer progression. His hope â€“ to connect research to patient care.

“Cancer is scary because it spreads,” Takabe says. “If we can figure out how breast cancer does that, we can be hopeful to prevent it.”

His research focuses on hypothesis that S1P, a lipid mediator — plays a critical role in the spread of breast cancer. It’s important to note that it’s a lipid and not a protein, Takabe says, because the role of lipids in cancer is vastly understudied to date compared to proteins.

Takabe says S1P plays a role in the development of new blood and lymphatic vessels in response to cancer progression. This could provide tubes through which breast cancer can spread to the lymph nodes and beyond.

“That’s the science part of it,” Takabe said. “But we want the science to be useful. What we’re talking about is how a lump can spread. And, more importantly, how can we stop it?”

The drug, which is called FTY720, has been approved by the Food and Drug Administration to treat multiple sclerosis. The VCU team wants to see whether the same drug, which targets S1P signaling, could also be effective in treating cancer, including breast cancer.

Studies of the effects of FTY720 on mice with breast or colon cancer have shown very promising results to slow down its progression. Takabe and his group are investigating the ideal condition to use this drug on patients through the start of a clinical trial.

A reluctant student of molecular biology two decades ago, Takabe now serves as an affiliate faculty member in the Department of Biochemistry and Molecular Biology. He sees his dual medical roles as a way to connect the dots.

“I am a surgeon who is doing research,” he says.

About VCU and the VCU Medical Center

Virginia Commonwealth University is a major, urban public research university with national and international rankings in sponsored research. Located in downtown Richmond, VCU enrolls more than 31,000 students in 222 degree and certificate programs in the arts, sciences and humanities. Sixty-six of the programs are unique in Virginia, many of them crossing the disciplines of VCU’s 13 schools and one college. MCV Hospitals and the health sciences schools of Virginia Commonwealth University compose the VCU Medical Center, one of the nation’s leading academic medical centers. For more, see www.vcu.edu.

“As an African-American woman, I am interested in reducing prevalence of HIV among African-American women,” said Belgrave.

The rate of new HIV infections is an estimated 15 times greater for African-American women than for white women, and more than three times greater than for Hispanic women, the Centers for Disease Control and Prevention reports. One in every 32 African-American women will be diagnosed with HIV.

Belgrave’s research expertise focuses on community and intervention-focused programs that use cultural aspects to promote well-being among African-American youth and young adults. She also directs the VCU Center for Cultural Experiences in Prevention.

Over the span of the project, a total of 650 students will be recruited to participate in programs teaching HIV and substance abuse prevention. Sisters Informing Sisters about Topics on AIDS (SISTA) is the proposed intervention curriculum for women. The culturally sensitive social skills training, led by peers, encourages condom use and provides condom negotiation advice, among other information. SISTA has been endorsed by the CDC as a proven, effective intervention program.

A different curriculum will be presented to young men. Both trainings will weave in substance abuse education and the role that alcohol and drug use play in sexual risk behavior.

Beyond the skills training, the research initiative will employ a social marketing environmental strategy, in collaboration with the VCU Wellness Resource Center, with educational posters placed in bathrooms at university locations frequented by large percentages of African-American students. In addition, the project will involve health fairs and forums held in conjunction with student organizations, and HIV testing and counseling services in partnership with the Fan Free Clinic.

“We will work with the national Center for Substance Abuse Prevention to evaluate the effectiveness of the program by collecting performance measures and by conducting process and outcome evaluations,â€ Belgrave said. â€œWe are in the middle of this project and program implementation, and data collection is ongoing.”

A version of this news article by Sathya Achia Abraham and the VCU Office of Public Affairs was published in August 2011.

About VCU and the VCU Medical Center

Virginia Commonwealth University is a major, urban public research university with national and international rankings in sponsored research. Located in downtown Richmond, VCU enrolls more than 31,000 students in 222 degree and certificate programs in the arts, sciences and humanities. Sixty-six of the programs are unique in Virginia, many of them crossing the disciplines of VCU’s 13 schools and one college. MCV Hospitals and the health sciences schools of Virginia Commonwealth University compose the VCU Medical Center, one of the nation’s leading academic medical centers. For more, see www.vcu.edu.

A child’s good oral health begins well before she cuts her first tooth. In fact, it starts before birth, with her mom.

Mothers-to-be and new mothers with untreated dental decay are much more likely to have children who develop dental decay, according to pediatric dentist Tegwyn H. Brickhouse, D.D.S., Ph.D., also a Virginia Commonwealth University researcher. Dental caries, tooth decay, is the single most common chronic childhood disease. Caries results when bacteria used to break down foods creates an acid in the mouth that harms tooth enamel.

“I work with mothers and children every day as both a clinician and child advocate,” said Brickhouse, the chair of the Department of Pediatric Dentistry in the VCU School of Dentistry, where she also serves as research director. “I understand the importance of oral health and its impact on overall health.”

Early childhood caries (ECC) disproportionately affects children from minority or low socioeconomic backgrounds. For that reason, Brickhouse plans to involve in her research 75 mother-child pairs enrolled at Family Lifeline of Richmond. The program assists Central Virginia’s most vulnerable children, parents and seniors by providing support, wellness and education.

“We hypothesize that certain maternal perinatal conditions can cause developmental disturbances in the formation of primary tooth structure and establishment of a microflora that in turn can lead to increased susceptibility to ECC,” said Brickhouse, the principal investigator of this research.

“We found that these high-risk mothers have an average knowledge of positive oral health behaviors but they do not understand the impact their oral health has on their child,” she added. “They don’t know at what age they should start brushing their child’s teeth and take their child for their first dental visit. Many mothers also have significant levels of dental decay in their own mouths.”

She started researching maternal influences on their infantsâ€™ oral health in 2008. This study, Maternal Influences and Prevention for Mothers and Infants in Early Childhood Home-Visiting Programs, aims to provide data on the influence of the mother’s history just before and after giving birth, dental literacy factors and maternal microbial transmission on dental disease in their infants.

Dental examinations and microbial sample collection have been completed on the mothers and infants.

This research would be the first, she said, to use high-throughput technology to conduct a molecular epidemiological study of mother/infant microbial profiles to better understand the mouth’s environment and the relationship microorganisms play in causing dental caries in infancy.

Virginia Commonwealth University is a major, urban public research university with national and international rankings in sponsored research. Located in downtown Richmond, VCU enrolls more than 31,000 students in 222 degree and certificate programs in the arts, sciences and humanities. Sixty-six of the programs are unique in Virginia, many of them crossing the disciplines of VCU’s 13 schools and one college. MCV Hospitals and the health sciences schools of Virginia Commonwealth University compose the VCU Medical Center, one of the nation’s leading academic medical centers. For more, see www.vcu.edu.

An antidepressant can alleviate symptoms of major depression in women experiencing or about to experience menopause, according to a study led by a Virginia Commonwealth University researcher.

The research compared the effectiveness and safety of the antidepressant desvenlafaxine, known as Pristiq, to a placebo in a double-blind trial led by Susan G. Kornstein, M.D., a professor of psychiatry and obstetrics/gynecology in the VCU School of Medicine. It was published in the Journal of Clinical Psychiatry.

In the United States, depression is approximately twice as common in women as in men. More than 20 percent of women will experience depression in the course of their lifetime, and depression seems to be influenced by reproductive events, such as the menstrual cycle, the postpartum period and menopause.

Research, including earlier work by Kornstein, has shown that women may respond to antidepressants differently from men and may also respond to medication differently at different times in their lives, she said.

“It’s really an assumption to say that because an antidepressant works for depression in general that it works for depression related to reproductive events,” she said. “This is the first large study testing the effectiveness of an antidepressant specifically in peri- and postmenopausal women with depression.”

Kornstein is an internationally recognized researcher in women’s mental health and depression at VCU who studies how depression affects women across their life span and the influence of the menstrual cycle and menopausal status on depression and its treatment.

Some women report mood swings, irritability, anxiety and depression in the years leading up to menopause, called the perimenopause. The reason for these emotional problems isn’t known, but the drop in estrogen levels that typically occurs during perimenopause and menopause may affect mood. The transition to menopause has been shown to be a high-risk period for major depression, in women both with and without a past history of depression.

Kornstein and colleagues evaluated Pristiq’s ability to alleviate major depression among women experiencing or about to experience menopause. The study enrolled 387 women who were peri-or postmenopausal and were diagnosed with major depression at 37 outpatient sites across the country. The women were randomly assigned to take either 100 mg or 200 mg daily of Pristiq or placebo for eight weeks.

The study found that women who took Pristiq showed significant improvement as measured by the 17-item Hamilton Depression Rating Scale and other psychological tests. The response rates were 58.6 percent for those taking Prstiq, compared to 38.2 percent for those on placebo. The drug was effective among the subgroups of perimenopausal women as well as those who were postmenopausal.

At the time the study started, the federal Food and Drug Administration had not yet approved Pristiq, which patients now typically take in 50 mg daily doses to treat depression. Kornstein said she is about to start recruiting patients for a new, similar study using the 50 mg daily dose.

Pristiq works by increasing the amounts of serotonin and norepinephrine, natural substances in the brain that help maintain mental balance. It is manufactured by Pfizer and was approved in 2008 to treat depression among adults. Wyeth, now a subsidiary of Pfizer, financially supported the study.

Kornstein, a consultant for Pfizer, is co-founder and executive director of the VCU Mood Disorders Institute and of the VCU Institute for Women’s Health, a groundbreaking center for treatment, research, education, and community outreach. She is also medical director of the VCU Clinical Trials Office. Her co-authors from Pfizer were Qin Jiang; Sujana Reddy, M.D.; Jeff J. Musgnung; and Christine J. Guico-Pabia, M.D., MBA, MPH.

About VCU and the VCU Medical Center

A version of this news article by Sathya Achia Abraham and the VCU Office of Public Affairs was published in August 2011. Virginia Commonwealth University is a major, urban public research university with national and international rankings in sponsored research. Located in downtown Richmond, VCU enrolls more than 31,000 students in 222 degree and certificate programs in the arts, sciences and humanities. Sixty-six of the programs are unique in Virginia, many of them crossing the disciplines of VCUâ€™s 13 schools and one college. MCV Hospitals and the health sciences schools of Virginia Commonwealth University compose the VCU Medical Center, one of the nationâ€™s leading academic medical centers. For more, see www.vcu.edu.

Several VCU investigators are focusing research efforts on health disparities among racial and ethnic populations, specifically looking at preterm births. Despite improvements to the nation’s general health, African-American women experience adverse pregnancy outcomes much more frequently than whites, resulting in infant death rates that are more than twice those of the white population.

“We have three main research themes: the identification of genetic factors that predict preterm births; the role of the vaginal microbiome in preterm birth; and the discovery of epigenetic and environmental factors that contribute to preterm birth,” said Jerome F. Strauss III, M.D., Ph.D., dean of the VCU School of Medicine, who is leading the research on maternal and fetal genomes.

Kimberly Jefferson, Ph.D., associate professor of microbiology and immunology, is leading the research on the role of infection within the vagina, and Timothy P. York, Ph.D., assistant professor of human and molecular genetics, is working on the epigenetic studies. The three themes are interrelated, according to Strauss, and the research teams are using a collaborative approach in studying this complex problem.

“This is the first major study to quantify the role of genetic factors and the environment in preterm birth in different populations. In addition, the vaginal microbiome is being comprehensively investigated so the role of specific microorganisms in preterm birth can be elucidated,” said Strauss.

A long-term aim is to determine how environmental factors, such as infection, interact with the genome to promote prematurity. The microbiome is a community of microorganisms, or microbes, inhabiting the human body. They inhabit almost every part of the human body, including on the skin, in the nose, mouth and gut, and in the urogenital area. Sometimes they cause sickness, but most of the time the microorganisms live in harmony with their human hosts, even providing vital functions essential for human survival. Researchers at VCU are studying how microorganisms found in the vagina influence health and disease in women.

The research team at VCU has also identified a genetic variant that may account for the higher rates of premature delivery experienced by African-American women compared with European-American women. The findings may help physicians identify patients who might benefit from therapeutic interventions and preventative measures, including lifestyle change or medical therapy to reduce the risk of premature birth.

Virginia Commonwealth University is a major, urban public research university with national and international rankings in sponsored research. Located in downtown Richmond, VCU enrolls more than 31,000 students in 222 degree and certificate programs in the arts, sciences and humanities. Sixty-six of the programs are unique in Virginia, many of them crossing the disciplines of VCU’s 13 schools and one college. MCV Hospitals and the health sciences schools of Virginia Commonwealth University compose the VCU Medical Center, one of the nation’s leading academic medical centers. For more, see www.vcu.edu.